This K08 Mentored Clinical Scientist Development Award will provide necessary training for a dental academic career track within a highly supportive multidisciplinary Health Science Center environment for the rapid transition of Dr. Papagerakis to an independent clinician scientist. The five year training plan consists of three inter-related components: (1) advanced training in state-of-the-art molecular craniofacial genetics and gene regulation through a well-planned research proposal; (2) clinical training in an Orthodontics residency program; and (3) training in the diagnosis and dental treatment of patients with craniofacial genetic diseases. Research related to the human disease cleidocranial dysplasia (CCD) will be pursued concomitant with clinical training leading to a certificate in Orthodontics. The candidate will participate in the Craniofacial Genetics Clinic working with multidisciplinary team members. In the last year of the award an NIDCR R01 application will be submitted. The major research focus of the candidate is to determine the molecular mechanisms by which mutation(s) in the RUNX2 transcription factor cause the tooth and bone phenotypes associated with CCD. Unique resources available for this study are dental pulp and periodontal ligament cell lines derived from CCD patients and normal age matched individuals. Preliminary studies have demonstrated that critical transcription factors for normal tooth development, LEF-1, is expressed in normal dental cells, but not in CCD dental pulp cells, suggesting that the lack of expression of this factor may play a role in development of the CCD phenotype. The hypotheses to be tested are 1) LEF-1 is expressed during late odontogenesis and periodontal tissue formation; 2) LEF-1 altered expression results in the CCD dento-alveolar phenotype; 3) RUNX2 controls LEF-1 dental and periodontal tissue expression. The specific aims to investigate these hypotheses are 1) to identify the extent to which LEF-1 is co-expressed with RUNX2 in dental/periodontal cell populations; 2) to analyze in vitro the specificity and complexity of RUNX2 regulation of LEF-1 gene; 3) to correlate in vitro findings with the in vivo dental phenotype and Lef-1 expression in RUNX2 transgenic mice knock out model. The long-term goal of this project is to achieve combined research and clinical training in the area of craniofacial genetics, in order to prepare Dr. Papagerakis for a successful career as a productive independent investigator.